Novel 2-aryl-1,3-indandiones and 2-aryl-2,3-dihydrobenz(f)indene-1,3-diones

ABSTRACT

NOVEL 2 - ARYL-1,3-INDANDIONES AND 2-ARYL-2,3-DIHYDROBENZ(F)INDENE-1,3-DIONES AND THEIR USE IN LOWERING THE BLOOD LIPID LEVEL IN MAMMALS.

United States Patent 01 "mice 3,784,606 Patented Jan. 8, 1974 U.S. Cl.260--590 3 Claims ABSTRACT OF THE DISCLOSURE Novel 2aryl-1,3-indandiones and 2-aryl-2,3-dihydrobenz[f]indene-l,3-diones andtheir use in lowering the blood lipid level in mammals.

This application is a division of copending application Ser. No.756,324, filed Aug. 29, 1968, now U.S. Pat. No. 3,622,632.

BACKGROUND OF THE INVENTION This invention relates to novel2-aryl-l,3-indandiones and 2-aryl-2,3-dihybrobenz[f]indene-1,3-dionesand their use in lowering the blood lipid level in mammals.

Atherosclerosis, a form of arteriosclerosis, is characterized byinternal thickening of the major blood vessels due to localizedaccumulation of lipids, of which cholesterol and other p-lipoproteinssuch as the triglycerides comprise the major constituents. It has alsobeen found that those suffering from the disease exhibit abnormally highblood cholesterol levels. While the etiology of the disease is not fullyunderstood, it is believed that the fl-lipoproteins, in particularcholesterol, play an important role in the disease.

In the advanced stages of the disease, plaques, comprising cholesteroland other B-lipoproteins, accumulate in the aorta, coronary, cerebral,and peripheral arteries of the lower extremities. As these plaquesincrease in size, the danger of fibrin deposition, possibly resulting inthrombosis and occlusion, is enhanced.

While no established method has been found for preventingatherosclerosis, it has been recommended that dietary habits be observedthat will ensure low p-lipoprotein levels. Besides stringent dietarymanagement, various therapeutic agents such as estrogens, thyroxineanalogs and sitosterol preparations have been used to lower thecholesterol levels of those afilicted with the condition.

It has now been found that various 2-aryl-1,3-indandiones and2-aryl-2,3-dihydrobenz[f]indene-1,3-diones are eifective hypolipemicagents because of their ability to lower the blood lipid level ofmammals. Consequently, these compounds can be expected to be useful inthe treatment of atherosclerosis and related cardiovascular diseaseswhich are associated with elevated blood lipid levels.

We have also found that some of the compounds described herein alsopossess a high degree of anti-inflam matory activity in mammals and areeifective in preventing and inhibiting the formation of granulomatoustissue.

Consequently, these particular compounds are expected] to be of value inthe treatment of those arthritic disorders that are responsive to theadministration of anti-inflammatory agents.

Although some 2-aryl-1,3-indandiones have been reported in the prior artto exhibit anti-inflammatory activity, many of them also inhibit bloodcoagulation. Indeed, 2-aryl-1,3-indandiones have been used in man asanticoagulants, e.g., 2-phenyl-1,3-indandione. Nevertheless, the use ofanti-coagulants is associated with a considerable amount of risk. Suchcompounds can cause fatal hemorrhaging even when average dosage levelsare employed. In this respect, it should be noted that some of thesecompounds have even been used as pesticides, e.g., 2-pivalyl-1,3-indandione (Pival) is used as a rodenticide. Accordingly, it wouldnot be desirable to employ a 2-aryl-1,3- indandione for a therapeuticuse if in addition it also inhibits the coagulation of blood, i.e.,inhibits prothrombin synthesis.

The present invention describes a series of 2-ary1-1,3- indandiones and2-aryl-2,3-dihydrobenz[f]indene 1,3- diones which lower the blood lipidlevel in mammals without exhibiting the objectionable property ofinhibiting the coagulation of blood. Further, some of the novelcompounds of the instant invention are also elfective antiinflammatoryagents and have been described in J. Med. Chem., 11, 342 (1968).

SUMMARY OF THE INVENTION This invention comprises a series of novel2-aryl-1,3- indandiones having the formulae:

where R1 is OH, '-NH2, OCH2C02H, (CH5)2NCH2CH20, -CF3, 0r SO2CF3; R andR? are CH O-, OH, SO Na, or (CH N50 provided that R and R are not both0CH R is 'Br, NO CF or -NH,,; R is methoxyphenyl, bromophenyl,trifluoromethylphenyl, trifiuoromethyl-sulfonylphenyl, or Z-naphthyl; Ris methoxyphenyl, 3-chlorophenyl, bromophenyl,trifluoromethylsulfouylphcnyl, or 2-naphthyl; R' is NO,, or CF and R iso-, m-, and p-tolyl This invention also comprises a series of2-aryl-2,3- dihydrobenz[f]indene-1,3-diones having the formula:

where R is tolyl, bromophenyl, iodophenyl, trifluoro-, methylphenyl,methoxyphenyl, trifluoromethylsulfonylphenyl, or 2-naphthyl.

The novel compounds of the present invention eflectively lower the bloodlipid level in mammals and are expected to be useful in the treatment ofatherosclerosis and related cardiovascular diseases which areassociatedwith also exhibit anti-inflammatory activity and are expectedto be of value in the treatmentfof those arthritic disorders that areresponsive to the administration of anti-inflame matory agents. i

' Furthermore, unlikernany of the known compou d's'jin the2-aryl-1,3-indandione series, the compounds of the. present invention donot have the objectionable property of inhibiting prothrombimsyn'thesis.DETAILED DESCRIPTION. OF THE INVENTION:

The novel compounds of'the present inventiod'canbef prepared by threepreviously described procedures. Of the" greatest utility for preparinganalogs with no substit ijents in the indane ring is the method of S. L.Shapiriif Kff Geiger, I. Youlus andL. Freedman, J. Org. Chem, 26, 3580(1961), which isoutlined in Chart I. i

In this synthetic scheme, a solution of sodium methoxide in methanol isadded to a mixture of benzaldehyde and phthalide contained in anhydrousethyl propionate. The resultant mixture is stirred at about 55 C. for 2hours, cooled and the solvent removed. The residue is dissolved in waterand the resultant solution extracted with ether. Acidification of theaqueous phase provides the 2-aryl-l,3- indandione, which is separatedand recrystallized from an appropriate solvent.

Since substituted phthalic acids are more readily accessi'ble thansubstituted phthalides, a second preparative method was used whichinvolves the condensation of an arylacetic acid with a substitutedphthalic anhydride fol-" lowed by rearrangement of thecondensationproduct in sodium methoxide solution. The synthetic schemeoutlined below in Chart II. 1 i

" CHART 1r X==Br, CP and CH In this procedure the approp anhydride andarylacetic acid are heated together-under nitrogen with anhydroussodiurntacetate at 270-275? riately substituted phtliahc:

l .b I h I k i I "'fo'r'several hours. The crude condensation produc srema r m than lson ai sodium o ideth reaction mixture evaporated todryness, and the residue dissolved in water and the resultant solutionextracted several times with ether. The aqueous phase is acidified andthe 2-aryl-1,3-indandionethat separates is collected and recrystallizedfrom anappropriate solvent. This procedure is also u'se d to prepare the2-aryl-2,3-dihydrobenz[ f]in-' dene-1,3-dione's. I With the 3 and,4-nitrophthalic anhydrides, the milder procedure of V. Oskaja and G.Vanays reported inLatvijas PSR Zinatmi Akad. Vestis, No.' 6,57 (1961);Chem.

Abstr., 56, 58 95 1962); ibid., No. 1, 81 (1962); Chem. Abstr., 59, 7439(l9 63 )r, which is outlined in Chart III,

i5 is used. A

' CHART III I A020 N0 0 ArCHgCOrH EtIN 11+ NO I A mixture of thenitrophthalic anhydride, phenylacetic acid, acetic anhydride, andtriethylamine is warmed on a steam bath, cooled and poured onto amixture of ice and concentrated hydrochloric acid. The product isseparated, dissolved-in-aqueous sodium hydroxide, and the resultantsolution washed with ether. The aqueous phase is acidifiedand'the2-aryl-'l;3-indandi01ie'i's separated and recrystallized from anappropriatesolvent. "Most of the phthalic anhydrides, arylacetic acids,and tion of the novel compounds of the present invention have eitherbeen reported in the prior art, or are readily synthesized byconventional procedures well known to those a. skilledin the art.

Almost all of the indandiones are isolated as their enol form, asevidenced by their deep red-violet colon-Followingrecrystallization frompolar solvents suchas ethanol, the IR spectra (KBr) of most of thesecompounds exhibits'a.single carbonylabsorption band near 61011. and thedicative of the diketo form.

While the compounds of the present invention are named and depicted as1*,3-diones, it is to be understood 3;,that'the corresponding enols andketo-enol equilibrium"; mixtures'are embraced within theclassifica'tionscheme usedhereim v I As previously mentioned, the novel compounds ofthe present invention are effective hypolipem'ic agents, i.e.,

. they lower the blood'lipid level of mammals. This propeach comprising4*;animals, of normal Sprague-Dawley (Charles River) male rats weighingfrom -220 g. are

benzaldehydes used as starting materials in the prepara- UV spectradetermined in methanol or methanol-sodium bonyl absorption bands at 5.73(m) and 5.81 s (s), in-

erty has been dramatically demonstrated in rats. Groups,

fed rat chow containing' 0.25% of the compounds described hereinfor twoovernightfeeding periods. On the morning of the third day the animalsare anesthetized and f bled from the abdominal aorta. The total plasmacholesterol is then determined by the method of J. J. Carr and I. I.Drekter reported in Clin. Chem., 2, 353 (1956). The plasma cholesterollevel of the treated animals is found to be significantly reduced, whencompared to animals not receiving the test compound.

The ability of the herein described compounds to lower the bloodtriglyceride level is illustrated by administering the compounds todogs. A dosage level of 50 mg./kg. of the compound, in gelled capsules,is administered to dogs twice a-gday. This treatment is continued over aperiod of 2 weeks andon every second day, the cholesterol andtriglyceride blood levels are determined. The cholesterol level isdetermined by the methodgiven above, and the triglyceride level ismeasured by the method of E. Van

Handel and Dr B. Zilversmith, reported in J. Lab. & Clin.: 1

Med., 50, 152 (1957). s;

Comparison of the blood triglyceride levels of dogs receiving the testcompounds shows a significant reduction as compared to the triglyceridelevels of untreated animals.

For oral administration in capsule form, the preferred excipients arelactose and high'molecular weight polyethylene glycols. When aqueoussuspensions are desired, the essential active ingredients are combinedwith emulsifying ingredients and/or suspending agents. Diluents such asethanol, propylene glycol, glycerine and various combinations ofdiluents are employed.

A typical human dosage form for oral administration is as follows:

Mg. 2-aryl-1,3-indandione 250 Corn starch, dry 17.50 Lactose 163.50Magnesium stearate 17.10 Sodium lauryl sulfate 1.90

The compounds described herein can be administered parenterally as wellas orally. For parenteral administration, solutions of the activeingredients in combination with other solutes such as glucose or salineare used. Such aqueous solutions should be suitably buffered, ifnecessary, to render then isotonic.

The dosage required to lower the blood lipid level will be determined bythe nature and the extent of the symptoms. Generally, small dosages willbe administered initially with a gradual increase in dosage until theoptimum level is determined. It will generally be found that when thecomposition is administered orally, larger quantities of the activeingredient will be required to produce the same level as produced by asmaller quantity administered parenterally. In general, from about 50 to500 mg. of active ingredient per kilogram of body weight administered insingle or multiple dosage units significantlylowers the blood lipidlevel. In generaL-when administered.

the lastIdose;-.blood samples were drawn into oxalatd' syringes from,the descending aorta' ,.while the animals were maintained" under lightpentobarbital anesthesia. Plasma was separated by centrifugation, :andprothrombin time was determined automatically with a Model 2-02-ClotTimer (Mechrolab Inc.) using thromboplastin extract (Simplastin,Warner-Chilcott, Morris Plains, NJ.) as directed by the manufacturer.

In Table I are listed some of the data obtained with known compounds inthe series as well as data obtained for some of the novel compounds ofthe present invention.

TABLE I Prothrombin time Compound: in rats 1 (l) 2-phenyl-l,3-indandione(2) 2-(1'-naphthyl)-1,3-indandione (3)2-(4-methoxyphenyl)-1,3-indandione (4)2-(3'-chlorophenyl)-l,3-indandione (5) 2-(4'-nitrophenyl)-1,3-indandione(6) 2-phenyl-5-bromo-1,3 indandione (7) 2-phenyl-5-nitro-l,3-indandione(8)' 2-(3'-nitrophenyl)-1,3 indandione (9)2-(2rhydroxyphenyl)-1,3-indandione (l0) 2 (4-acetamidophenyl)1,3-indandione (l1) 2-(4'-hydroxyphenyl)-l,3-indandione (12) 2-(3'methoxyphenyl)-5-methyl1,3-indandione (13) 2 (2'naphthyl)-5-bromo-1,3-indandione (14) 2 (3'trifluoromethylphenyl)-4-nitro- 1,3-indandione (l5) 2-(2'-naphthyl) 5trifluoromethyl-LS- indandione 1 prolongation of prothrombin time 1'6hours after administration of nine oral doses, 8 hours apart (100mg./kg. p0) prolongation of prothrombin time 16 hours afteradministration of two oral doses, 8 hours apart (100 mg./ kg. p0) noprolongation of prothrombin time after nine oral doses (100 mg./kg. p0).

Compounds (1)-(7) listed in Table I have been previously described inthe prior art and all of them have the undesirable property ofinhibiting prothrombin synthesis. On the other hand, compounds (8)-(15),now described for the first time, do not inhibit prothrombin synthesis 0o l CH; R HQ H and where R is methoxyphenyl, 3-chlorophenyl,bromophenyl, tricfluorom'ethylsulfonylphenyl or 2-naphthyl;

R is 0-, m-, and p-tolyl; and v Z is CF or CF SO2-(3'-nitropheny1)-1,3-indandione2-(3-methoxyphenyl)-5-methyl-1,3-indandione2-(2-naphthyl)-5-bromo-l,3-indandione2-(3'-methylphenyl)-5-trifiuoromethyl-1,3-indandione2-(2'-naphthyl)-5-trifiuoromethyl-1,3-indandione.

The anti-inflammatory activity of these compounds is determined by theinhibition of edema formation in the 7 hind paw of rats (Charles Riverstrain; average weight 170 g.) in response to a sub-plantar injection ofcarrageenin (rat-foot edema test). The experimental procedures followedare those of Winter et al., as reported.

Statham Pressure Transducer. The output from the transducer is fedthrough a control unit to a microvoltameter. The volume of mercurydisplaced by the immersed. paw is read. Drugs are given by gavage. Onehour after drug administration, edema is induced by injection of 0.05ml. of 1% solution of carrageenin into the plantar tissue of the markedpaws. Immediately thereafter, the volume of the injected foot ismeasured. The increase in foot volume 3 hours after the injection ofcarrageenin constitutes the individual response. The increase in volumeof the feet of drug-treated animals are compared with those justreceiving vehicle alone.

The results obtained for some of the compounds of the present inventionare tabulated in Table II.

TABLE II Rat foot edema test Inhibition of edma formation as comparedwith 1 Anti-inflammatory activity is reported as a mean inhibition ofedema in the treated animals within the range of 0.5-1.5 times that ofthe mean inhibition of concurrently treated animals receiving aspirin(100 mg./kg. p) drug given at 100 mg./kg.; drug given at 33 mg./kg.;drug given I: mg./kg. po.

As can be seen by examination of Table H, some of the novel compounds ofthe present invention are effective anti-inflammatory agents and, aspreviously mentioned,

have the further pharmacological advantage of not in- 65 hibitingprothrombin synthesis. These compounds are expected to be useful inalleviating the swelling and inflammation exhibited by arthritic andrheumatic subjects. They can be administered either alone or in combinations with pharmaceutically-acceptable carriers. The proportion ofactive ingredient to carrier is determined by the solubility andchemical nature of the compound,

chosen route of administration and standard pharmaceutical practice. Fororal administration in capsule form, preferred excipients are lactoseand high molecular weight polyethylene glycols. When aqueous suspensionsarein Table HI are also prepared according to the above desired, theessential active ingredients are combined with emulsifying and/orsuspending agents. Diluents such as; ethanol, propylene glycol,glycerine and variouscombina: tions of diluents are employed. Forparenteral administra-,' tion, solutions of the active ingredientsincombination with other solutes such as glucose or saline are used.Such aqueous solutions should be'suitably buffered, if necessary,torender them isotonic. v

The dosage required to reduce inflammation and swelling in arthriticandrheumatic subjects will be determined by the nature and the extent ofthe symptoms. Generally, small dosages will be administered initiallywith a gradual increase in dosage until the optimum level isdetermined.It will generally be found that when the composition is administeredorally, larger quantities of the active ingredient will be required toproduce the same level as produced by a small quantity administeredparenterally. In general, from about 1 to 100 mg. of active ingredientper kilogram offbody weight administered in single or multiple dosageunits effectively reduces inflammation and swelling in; arthritic andrheumatic subjects.

The following examples are provided to more fully illustrate the presentinvention, but are not to be construed as limiting .the scope thereof inany way.

EXAMPLE I To a mixture of 1 mole of 3-nitrobenzaldehyde, 1 mole ofphthalide, and 480 ml. of dry ethylpropionate is rapidly added 3 molesof sodium methoxide in 700 ml. of methanol..The reaction mixture isstirred at C. for 2 hours, cooled, and the solvent removed under reducedpressure. The residue is dissolved in 5.5 liters" of water and themixture extracted with ether and filtered. The filtrate is acidified toa pH of about 2 and the2-(3'-nitrophenyl)-l,3- indandione is filteredand recrystallized from methyl ethyl ketone. The yield is 49%; M.P.224226 C.

Analysis.Calcd for C H NO (percent): C, 67.40; H, 3.39; N, 5.24. Found(percent): C, 67.58; H, 3.64; N,' 5.19.

Using the appropriate starting materials, the compounds procedure. 7

TABLE III Crystalliza- Yield,

2-aryl-1,3-indand1one tion solvent percent M.P., C.

Z-(earboxymethoxyphenyl) -1,3- Ethanol- 64 198. 53-200. 5 aii a fn i ih1 mi th (1 78 I me ya me oxy- 0...": 230-232 phenyl)-1,3-indandione.2-(4-acetamidophenyl)-1,3-indo 54 239-241 dandione. j I2(4-methoxy-3-sodiun1 sulfodo 9 286-288 pheny1)-1,3-indandione.2-(4-methoxy-3-dimethylsulamyldo 15 185.5-1815.

phenyl)-1,3-indandione.

1 Decomposed.

EXAMPLE It (A) 2-(2'-methoxyphenyl)-l,3-indandione is preparedaccordingto the procedure of Example I from the appropriate startingmaterials. Yield: 71%; crystals from HBr acid for 3 /2 hours. Aftercooling, the dark red solids are filtered and recrystallized froma smallamount of ethanol to yield 2-(2-hydroxyphenyl)-l,3-indandione. Yield:0.34 g. (39%); M.P.,218'-223 C.

Analysis.'-Calcd for C H O (percent): C, 75.62; H, .4123. Found;(percent): C, 75.5 8; H, 4.42. I L

EXAMPLE III (A) 2 (4' methoxyphenyl)-1,3-indandione is preparedaccording to the procedure of Example I from the appropriate startingmaterials. M.P. 154155.5 C.

(B) 2 (4' hydroxyphenyl) 1,3-indandione is prepared from2-(4'-methoxyphenyl)-1,3-indandione according to the procedure ofExample II(B). Yield 64%; crystals from methanol, M.P. 259-260" C.

Analysis.-Calcd for C H O (percent): C, 75.62; H, 4.23. Found (percent):C; 75.93; H, 4.28.

EXAMPLE IV (A) 2 (3,4' dimethoxyphenyl)-1,3-indandione is preparedaccording to the method of Example I from the appropriate startingmaterials. Yield: 65%; crystals from ethanol, M.P. 190.5-192.5 C.

Similarly, using the appropriate starting materials the followingcompounds are also prepared:

2- (3 -carboxymethoxyphenyl) 1, 3 -indandione 2- 3'19-dimethylaminoethoxyphenyl)-1,3-indandione2-(2'-acetamidopheny1-1,3-indandione2-(3-acetamidophenyl)-1,3-indandione2-(3-trifluoromethylphenyl)-1,3-indandione2-(4'-trifluoromethylphenyl)-1,3-inclandione 2- (3'-trifluoromethylsulfonylphenyl) 1, S-indandione 2-(4'-trifiuoromethylsulfonylphenyl)-1,3-indandione 2-(4'-hydroxy-3-s0dium sulfophenyl)-1,3-indandione2-(3'-hydroxy-4'-dimethylsulfamylphenyl)-1,3-

indandione 2-(3',4-di-sodium sulfophenyl)-1,3-indandione 2-3-dimethylsulfamyl-4-sodium sulfophenyl)-1,3-

indandione 2- (3 ',4'-di-dimethylsulfamylphenyl) -1,3-indandione2-(3'-methoxy-4'-sodium sulfophenyl)-1,3-indandione 2- (3'-methoxy-4-dimethylsulfamylphenyl 1, 3-

indandione.

(B) 2 (3',4 dihydroxyphenyl)-1,3-indandione is prepared from2-(3',4-dimethoxypheny1)-1,3-indandione according to the procedure ofExample II(B). Yield: 11%; crystals from acetic acid-Water, M.P. 252-254dec.

Analysis.-Calcd for C H O (percent): C, 70.97; H, 3.96. Found (percent):C, 70.97; H, 4.14.

EXAMPLE V A suspension of 2.8 g. (0.010 mole) of2-(4'-acetamidophenyl)-1,3-indandione is refluxed in 100 ml. of 6 N HClfor 4 hours. After filtration, the collected solids are dissolved inaqueous sodium hydroxide and the red solution is acidified with aceticacid to a pH of 6. The red precipitate is filtered and recrystallizedfrom ethanol to give 0.76 g. (28%) of 2-(4-aminophenyl)-1,3-indandione;M.P. 227-229 C.

Ainulysis.-Calcd for C H NO (percent): C, 75.93; H, 4.67. Found(percent): C, 76.20; H, 4.80.

EXAMPLE VI 0.10 mole of 2-(3',4'-dihydroxyphenyl)-1,3-indandione isdissolved in about 300 ml. of a 1 molar sodium hydroxide solution and0.10 mole of dimethyl sulfate is slow- 1y added \m'th stirring. Thesolution is stirred at about 50 C. for /2 hour, cooled, filtered andacidified to a pH of about 2 with hydrochloric acid. The mixture of2-(3'- hydroxy 4' methoxyphenyl) 1,3-indandione and 2 (3' methoxy 4hydroxyphenyl) 1,3 indandione is separated and purified by columnchromatography on silica gel or alumina.

EXAMPLE VII 4-bromophthalic anhydride is prepared by refluxing asolution of 3.7 g. (0.015 mole) of 4-bromophthalic acid for 2 hours in50 ml. of acetic anhydride containing 1 drop of sulfuric acid, followedby evaporation of the mixture to dryness. To the crude anhydride isadded 2.8 g. (0.015 mole) of Z-naphthylacetic acid and 50 mg. ofanhydrous sodium acetate. The solid mixture is heated under nitrogen at275 C. for 2 hours. Upon cooling, a brown solid is obtained which istriturated with 10% sodium bicarbonate and dried under vacuum. The driedcrude solid is rearranged in 100 ml. of refluxing methanol containing2.1 g. (0.039 mole) of sodium methoxide. After 1 hour, the reactionmixture is evaporated to dryness and the residue dissolved in water. Theaqueous solution is extracted several times with ether and the aqueouslayer is acidified with 6 N HCl acid. The crude red precipitate of 2 (2'naphthyl)-5-bromo-l,3-indandione is recrystallized from ethanol to yield2.5 g. of product (47%); M.P. 180.5-181-5 C.

Analysis.Calcd for C H BrO (percent): C, 64.97; H, 3.16. Found(percent): C, 64.63; H, 3.26.

Using the above procedure and the appropriate starting materials, 2 (3trifluoromethylphenyl)-5-bromo-1,3- indandione is similarly prepared in27% yield; M.P. 154- 155.5 C. (ethanol).

Analysis.-Calcd for C H BrF O (percent): C, 52.06; H, 2.18. Found(percent): C, 51.86; H, 2.17.

Similarly, the following compounds are prepared from the appropriatestarting materials:

2- 4'-methoxyphenyl)-5-bromo-1,3-indandione 2- (3'-methoxyphenyl)-5-bromo-1,3-indandione 2- (2'-bromophenyl) -5-bromo-1,B-indandione 2-(4'-trifluoromethylsulfonylphenyl) -5-bromo-1,3-

indandione 2- (3 '-trifiuoromethylsulfonylphenyl) -5-bromo-1,3

indandione.

3-bromophthalic anhydride is prepared from 3-bromophthalic acid by theabove procedure and used to prepare the compounds below:

2-(2'-naphthyl)-4-bromo-1,3-indandione2-(3-trifluoromethylphenyl)-4-bromo-1,3-indandione 2- 4'-methoxyphenyl)-4-bromo- 1, 3 -indandione 2- 3 '-methoxyphenyl) -4-bromo- 1,3-indandione 2- 2'-bromophenyl) -4-bromo- 1,3-indandione 2-(4'-trifluoromethylsulfonylphenyl) -4-bromo-1,3-

indandione 2- (3 -trifluoromethylsulfonylphenyl) -4-bromo-1 ,3-

indandione.

EXAMPLE VIII A solution of 0.05 mole of 3-nitrophthalic anhydride, 0.05mole of 3-trifluoromethylphenyl acetic acid, 1.8 moles of aceticanhydride, and 0.15 mole of triethylamine is warmed on a steam bath for15 minutes. After cooling, the reaction mixture is poured onto a mixtureof ice and concentrated hydrochloric acid. The resultant gummy solid isseparated, dissolved in aqueous sodium hydroxide, and the resultantsolution washed with ether. The cooled aqueous layer is acidified with 6N hydrochloric acid and stirred at 0 C. to provide crude2-(3'-trifluoromethylphenyl) 4 nitro 1,3-indandione in 19% yield; M.P.174-176.5 C. (ethanol).

Analysis.-Calcd for C H F NO (percent): C, 57.20; H, 2.40. Found(percent): C, 57.50; H, 2.77.

Using the appropriate starting materials, the following compounds aresimilarly prepared.

2-(3'-methoxyphenyl)-4-nitro-1,3-indandione2-(4'-methoxypheny1)-4-nitro-1,3-indandione 2- (2'-b romophenyl)-4-nitro- 1,3 -indandione 2-(4'-bromophenyl)-4-nitro-1,3-indandione 2-(3 '-trifluoromethylsulfonylphenyl) -4-nitro-1,3-

indandione 2- 2'-naphthyl) -4-nitro-1 ,3-indandi0ne 2- (3'-methylphenyl) -4-nitro-1,3-indandione 2- (4'-methylphenyl) -4-nitro-1,3 -indandione.

Using S-nitrophthalic anhydride in the above reaction instead of4-nitrophthalic anhydride, the compounds in Table IV are prepared fromthe appropriately substituted phenylacetic acids:

indandione. 2-(2'-naphthyl)-5-nitro-1,3-indandione.

Likewise, the following compounds are also prepared:

2- (4'-methoxyphenyl)-5-nitro-l,3-indandione2-(3'-bromophenyl)-5-nitro-1,3-indandione 2-4-trifluoromethylsulfonylphenyl) --nitro- 1,3-

indandione.

EXAMPLE 1X Dry nitrogen is bubbled into a solution of 0.01 mole of 2(3'-trifluoromethylphenyl)-4-nitro-1,3-indandione in 150 ml. of absoluteethanol. After the addition of 0.045 mole of hydrazine hydrate, a smallportion of fresh Raney nickel catalyst is added. After stirring thereaction mixture for about 20 minutes at room temperature, a secondportion of catalyst is added. After an additional hour, excess catalystis added and the mixture is heated to boiling and filtered while hot.Acidification of the filtrate with 6 N hydrochloric acid and addition ofwater provides crude 2 (3'trifluoromethylphenyl)-4-amino-l,3-indandione, which is crystallizedfrom ethanol.

Using the appropriate starting materials the following compounds aresimilarly prepared:

2-( 3 -methoxyphenyl) -4-amino-1,3-indandione 2- (4'-methoxyphenyl)-4-amino-1, 3 -indandione 2- 2'-bromophenyl) -4-aminol ,3 -indandione2-(4-bromophenyl)-4-amino-1,3-indandione 2- 3'-trifluoromethylsulfonylphenyl) -4-amino-1,3-

indandione 2-(2'-naphthyl)-4-amino-1, 3-indandione 2-( 3 '-methylphenyl)-4-aminol ,3-indandione 2-(4-methylphenyl)-4-amino-1,3-indandione 2- (3'-trifluoromethylphenyl) -5-amino- 1 ,3-indandione 2- 3 '-methylphenyl)-5-amino-1,3-indandione 2- (2'-naphthyl)-5-amino-1,3-indandione 2-(4'-methoxyphenyl)-5-amino-1,3-indandione 2- 3-bromophenyl)-5-amino-1,3-indandione 2-(4'-trifluoromethylsulfonylphenyl) -5-amino-1,3-

indandione.

EXAMPLE X 4-trifluormethylphthalic anhydride is prepared by refluxing4.7 g. (0.02 mole) of 4-trifiuoromethylphthalic acid in 50 ml. of aceticanhydride containing 1 drop of concentrated sulfuric acid for 4 hours.Evaporation to dryness under reduced pressure alfords the crudeanhydride as a dark solid; To the crude anhydride is added 8.2 g. (0.040mole) of 3-trifluoromethylphenylacetic acid and 400 mg. of anhydroussodium acetate. The mixture is heated at 275C. for 2 hours, undernitrogen, and the residue subjected to high vacuum for approximately 15minutes. The resdue is then combined with 25 ml. of methanol and asolution of 8.7 g. (0.16 mole) of sodium methoxide and 100 ml. ofmethanol. After refluxing for three quarters of an hour, and evaporationto dryness, the residue is dissolved in 300 ml. of water and extractedthree times with 200-ml. portions of ether. Owing to the influence ofthe two lypophilic trifluoromethyl substituents, the sodium salt of the1,3-indandione is exn'acted into the ether. Evaporation of the etherextracts affords the crude sodium salt, which is then dissolved in waterand the resultant solution acidified. The red2-(3'-trifluoromethylphenyl)-5-trifluoromethyl 1,3 indandione whichseparates from solution is filtered. Yield: 7.1 g. (50%); M.P. 129-131C.

12 Analysis.Calcd for C H F O (percent): C, 56.99; H, 2.25. Found(percent): C, 57.12; H, 2.59.

EXAMPLE XI A thorough mixture of 0.020 mole of 4-trifluoromethylphthalicanhydride, 0.020 mole of Z-naphthylacetic acid, and 200 mg. of anhydroussodium acetate, is heated under nitrogen at 270 C. for about 3 hours.After cooling, the residue is subjected to high vacuum for approximately15 minutes and dissolved in 50 ml. of methanol. To this solution is thenadded 4.3 g. (0.080 mole) of sodium methoxide in 30 ml. of methanol. Theresulting dark red solution is refluxed 1 hour, cooled, and evaporatedto dryness. The residue is dissolved in 150 ml. of water, and theresultant solution is acidified with 6 N HCl to afford crude2-(2'-naphthyl)-5-trifluoromethyl- 1,3-indandione. Yield: 27%; M.P.189.5191 C. (ethanol).

Analysis.-Calcd for C H F O (percent): C, 70.58; H, 3.26. Found(percent): C, 70.64; H, 3.60.

Using the above procedure, the compounds in Table V are prepared fromthe appropriate starting materials.

TABLE V Crystalllza- Yield,

2-aryl-1,3-indandlone tion solvent percent M.P., C;

2-(3 -methylphenyl)-5-trifluoro- Ethanol- 38 126-128methyl-1,3-indandlone. water. 2-(3-methoxyphenyl)-5-trlfluoro-Isopropanol- 33 166. 5-168 methyl-1,3-indandlone. water.2-(3-bromophenyl)-5-trifluoro- Ethanol- 19 172. 5-174methyl-1,3-indandione. water.

Similarly, the following compounds are also prepared:2-(4-trifluoromethylsulfonylphenyl)-5-trifluoromethyl- 1,3-indandione2-(3'-trifluoromethylsulfonylphenyl)-5-trifluoromethyl- 1,3-indandione2-(4-methylphenyl)-5-trifluoromethyl-l,B-indandione 2- (2-methoxyphenyl)-5-trifluoromethyl-1,3-indandione 2- (4'-bromomethyl)-5-trifluoromethyl-l ,3-indandione.

EXAMPLE XII 2-(3'-trifluoromethylphenyl) 4 trifiuoromethyl-l,3-indandione is prepared from 3-trifluoromethylphthalic anhydride and3-trifluoromethylphenylacetic acid according to the procedure of ExampleX.

EXAMPLE XIII The following compounds are prepared from 3-tri-,fluoromethylphthalic anhydride and the appropriately substitutedarylacetic acids according to the method of Example XI:

EXAMPLE XIV A thorough mixture of 0.030 mole of 4-methylphthalicanhydride, 0.030 mole of 3-methoxyphenylacetic acid, and mg. ofanhydrous sodium acetate is heated under nitrogen at 290 C. for 3 hours.The resultant product is triturated with. 75 ml. of 10% sodiumbicarbonate and filtered, and the filtered material is dried undervacuum over phosphorous pentoxide. Combination of the resulting drysolid with 15 ml. of methanol and 2.2 g. (0.045 mole) of sodiummethoxide in 50 ml. of methanol produces a red solution which isrefluxed for hour and TABLE VI Crystallization Yield, M.P.,2-ary1-1,3-1ndandlone solvent percent 0.

2-(2'-bromophenyl)-5-methyl-1,3- Ethano1 40 131-133 indandione.2-(3-chlorophenyl)-6-methy1-1,3 :-.---.do 72 123425 indandione.

The compounds below are also prepared according to the above procedurefrom the appropriately substituted starting materials:

2- (3 '-trifluoromethylsulfonyl) --methyl-1,3-indandione2-(2-naphthyl)-5-methyl- 1,3-indandione 2- (4'-bromophenyl) -5-methyl-1,3-ind andione 2- (4'-chlorophenyl) -5-methyl-1,3 -indandione2-(2-methoxyphenyl)-5-methy1-1,3 -indandione 2- 3 '-methoxyphenyl-4-methyll ,3-indandione 2- (3 '-trifiuoromethylsulfonyl) -4-methyl-1,3-indandione 2- (2-naphthyl) -4-methyll 3-indandione2-(4'-bromophenyl)-4-methyl-1,3-indandione 2-(4-chlorophenyl)-4-methyl-1,3-indandione 2-(2'-methoxyphenyl) -4-methyl-1,3-indandione.

EXAMPLE XV 2,3-naphth'alene dicarboxylic acid anhydride is prepared byrefluxing 4.3 g. (0.02 mole) of 2,3-naphthalenedicarboxylic acid in 50ml. of acetic anhydride containing 2 drops of concentrated sulfuric acidfor 2 hours. The mixture is evaporated to dryness and the resultinganhydride is thoroughly mixed with 3.0 g. (0.02 mole) of m-tolylaceticacid and 100 mg. of sodium acetate. The mixture is heated under nitrogenat 270 C. for 3 hours and cooled. To the resultant solid is added 20 ml.of methanol and a solution of 3.3 g. (0.06 mole) of sodium methoxide in50 ml. of methanol. After refluxing 1 hour and evaporating to dryness,the residue is dissolved in 250 ml. of Water and the solution extractedwith ether. The aqueous phase is acidified with 6 N hydrochloric acid,and the orange solid which separates from solution is recrystallizedfrom 1 liter of boiling acetone to give in several crops 2.2 g. (39%) of2-(3-methylphenyl)-2,3-dihydrobenz[f]indene-1,3-dione. M.P. 258-260 C.

Analysis.-Calcd for C H O (percent): C, 83.39; H, 4.94. Found (percent):C, 83.72; H, 4.95.

Using the above procedure, the compounds in Table VII are prepared fromthe appropriate starting materials:

14 The compounds below are also prepared according to the aboveprocedure from the appropriate starting materials: 2- (3 '-bromophenyl-2,3-dihydrobenz [f indene- 1 ,3-dione2-(4'-iodophenyl)-2,3-dihydrobenz[f]indene-1,3-dione 2-(2'-methoxyphenyl) -2,3-dihydrobenz [f indene- 1 ,3-

dione 2- 3 -trifiuoromethylsulfonylphenyl) -2,3-dihydro'benz-[f]indene-1,3-dione.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

where R and R are selected from the group consisting of CH 0- and 0H;provided that R and R are not both OCH;,.

2. A compound selected from the group consisting of those having theformula:

where R is selected from the group consisting of methoxyphenyl andtrifluoromethylsulfonylphenyl.

3. A compound selected from the group consisting of those having theformula:

where R is selected from the group consisting of tolyl, bromophenyl,iodophenyl, trifiuoromethylphenyl, methoxyphenyl,trifluoromethylsulfonylphenyl, and 2-naphthyl.

References Cited UNITED STATES PATENTS 2,938,925 5/1960 Molho 2605903,413,353 11/1968 Nauta 260-590 OTHER REFERENCES Horton et al.: ChemicalAbstracts, 54, 21002 (1960).

DANIEL D. HORWITZ, Primary Examiner

